According to incentive-sensitization theory of addiction, the critical change in addiction leading to compulsive drug pursuit is in the ability of drug-associated cues to engage a sensitized motivational response that, in turn, leads to enhanced drug pursuit. In this view, the problem is not the formation of aberrant and/or excessively strong associations between environmental cues and drug, but rather enhanced ability of drug-associated stimuli to engage brain motivational systems. Associations between a contextual conditioned stimulus and the drug unconditioned stimulus are formed in the basolateral amygdala. The conditioned place preference (CPP) paradigm models the formation of the associations between contextual cues and the rewarding effects of drugs of abuse and there is evidence to suggest that formation of associations between context and drug is accompanied by increased synapses in the basolateral amygdala (Rademacher et al. 2006). Activity-regulated cytoskeletal associated protein (Arc) is induced by acute psychostimulant administration (Tan et al., 2000) and behavioral experience that leads to long-lasting synaptic modifications (Kelly &Deadwyler, 2003). Importantly, there is a correlation between Arc protein expression in dendritic spines and the onset of synaptogenesis (Wang &Pickel, 2004). In this application, the hypothesis that amphetamine- (AMPH) induced CPP targets Arc to dendritic structures such as the spines of pyramidal neurons and/or dendrites of interneurons of the basolateral amygdala will be tested. If the data support this hypothesis, then memories for contextual cues paired with drug could be disrupted by blocking Arc, which would diminish drug-craving and drug-seeking behavior and decrease the probability of relapse. In Specific Aim 1, dual-label immunohistochemistry and laser-scanning confocal microscopy will be used to determine whether AMPH place conditioning alters Arc expression in basolateral amygdala pyramidal neurons and/or interneurons. In Specific Aim 2, light microscopy, a dual label immunoperoxidase/immunogold technique, electron microscopy, and unbiased stereology will be used to determine whether AMPH place conditioning alters Arc expression in dendritic structures of pyramidal neurons and/or interneurons in the basolateral amygdala. In human addicts, exposure to environmental cues previously associated with drug use strongly increases the risk of relapse. Developing effective treatments for addiction requires a better understanding of the neural substrates responsible for drug-seeking behavior. This proposal is intended to study how the neural circuitry in the basolateral amygdala is altered after repeated pairings between environmental context and drug.